PROJECT SUMMARY Glioblastoma multiforme (GBM) is a deadly disease with no effective therapy and is associated with one of the worst 5-year survival rates of all human cancers. Current treatments of GBM are largely ineffective due to the high propensity of GBM tumor recurrence, which is believed to be driven in part by the persistence of a specialized, stem-like population of GBM cells called tumor-initiating cells (TICs). Furthermore, transcriptional profiling has indicated that GBM recurrence is also associated with a proneural to mesenchymal transition (PMT), activating similar molecular programs to epithelial to mesenchymal transition and conferring pro- invasive mesenchymal features to GBM TICs, which exacerbate recurrent GBM. These post PMT TICs exhibit a highly invasive phenotype and readily infiltrate and spread through the brain parenchyma making it extremely difficult to eliminate via conventional treatments. Focused investigations of the mechanisms regulating enhanced GBM TIC motility represent a promising approach to developing effective GBM therapy. During PMT, cadherin switching occurs, upregulating the expression of the cell-cell adhesion protein cadherin-11, which leads to subsequent increases in cell migratory capacity and directional persistence. Current investigations indicate that cadherin-11 may promote invasion by two mechanisms: 1) by increasing the expression and activity of pro-invasion proteins p120 catenin (p120) and Rac1 GTPase, and 2) by transmitting intercellular tension generated between neighboring cells, which regulates actin organization and promotes cell directional persistence. Notably, recent data determined that cadherin-11 expression was dramatically increased in GBM tumors. This proposal seeks to elucidate the underlying contributions of cadherin-11 in GBM invasion by studying the role of cadherin-11 in proneural and mesenchymal GBM TICs. To do this, we will test the following hypotheses: 1) Cadherin-11 is responsible for GBM tumorigenesis and recurrence by promoting GBM TIC invasion through the modulation of p120 and Rac1 and through the increase in cell-cell tension; 2) GBM tumorigenesis and recurrence can be mitigated by targeting and disruption cadherin-11 signaling and biophysical function. The proposed studies will be the first to clarify the molecular and functional effect of cadherin-11 in GBM TIC invasion. They will also be the first to test the efficacy of cadherin-11 targeting as a potential therapy for GBM.